Liquid depot for non-invasive sustained delivery of agents to the eye

ABSTRACT

The present embodiments provide compositions, methods, and kits for the treatment or prevention of ocular conditions or maladies via non-invasive liquid depots. In at least one embodiment, the liquid depot is capable of sustained-release delivery of at least one pharmaceutical agent to the eye for days or weeks.

RELATED APPLICATION

The present application is a continuation of International ApplicationNo. PCT/US2019/030294, filed May 1, 2019, which claims priority benefitof U.S. Provisional Application No. 62/665,367, filed May 1, 2018, thedisclosures of which are hereby incorporated by reference in theirentirety for all purposes.

The present embodiments provide compositions and methods for thetreatment of ocular conditions or maladies.

BACKGROUND

There remains a need for noninvasive, sustained delivery ofpharmaceutical agents to tissues and liquid portions of the eye, such asthe conjunctiva, cornea, or aqueous humor.

SUMMARY

The present embodiments provide compositions and methods for treating orpreventing ocular ailments via a non-invasive liquid depot capable ofdelivering at least one pharmaceutical agent to the eye for days orweeks. This liquid depot is biocompatible and adapts to the shape of theeye, forming a thin film or flat bubble that covers the exterior tissuesof the eye (e.g., conjunctiva, corneal surface) and is resistant tolacrimation (e.g., tears); although this film remains in place for daysor over a week, it does not impair vision after initial instillation;and instillation is mediated, at least in part, by viscosity of theliquid depot; this depot formulation can be used to deliverpharmaceutical agent(s) to various parts of the eye where it can bedetected for over the course of days or in some circumstances, overthree weeks after a single administration. Remarkably, although thisliquid depot remains on the outside of the eye, pharmaceutical agent(s)can be delivered into ocular tissues (e.g., cornea) and fluids (e.g.,the aqueous humor) inside the eye for at least an entire day, at leastthree (3) days, and in some embodiments, at least seven (7) days. Assuch, effective intermittent administration (e.g., once a day, onceevery 3 days, or longer) of a single-dose liquid depot comprising atleast one pharmaceutical agent is made possible with the presentembodiments, in marked contrast to the multiple daily doses requiredwith current commercial ocular formulations.

The liquid depot described herein provides sustained release ofpharmaceutical agent(s) at a steadier release rate (i.e., decreased“spike”), fewer side effects, and/or with superior efficacy comparedwith current aqueous-based eye drops. In some embodiments, thecontinuous levels of pharmaceutical agent released from the liquid depotprovides efficacious benefit at C_(max) concentrations of pharmaceuticalagent below those previously thought to be required to achieve clinicalbenefit, based on comparison with current aqueous-based eye drops.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the amount of dexamethasone in the anterior chamberfollowing administration of a current commercial eye drop comprising0.1% dexamethasone.

FIG. 2 shows the average amount of dexamethasone in the anterior chamberof rabbit eyes following instillation of an example of a liquid depot ofthe present embodiments comprising dexamethasone. X-axis, days; y-axis,dexamethasone ng/mL.

FIG. 3 shows the average amount of vitamin E acetate in tear samplescollected from rabbit eyes on days 1, 4, 7, and 12 followingadministration of a single 50 μL depot of vitamin E acetate. During thissame time course, vitamin E acetate was not observed in samples ofaqueous humor. X-axis, days; y-axis, vitamin E acetate ng/mL.

FIG. 4 is a graph showing in vitro release of 5 mg dexamethasone powder(▴), 5 mg dexamethasone in MIGLYOL® 810 (♦), or 5 mg dexamethasone invitamin E acetate (▪) in saline. Powder or 50 μL aliquots of liquiddepot formulations were placed in 100 mL saline (50 mL exchange), and %dexamethasone release determined by UPLC. X-axis days; y-axis % totaldexamethasone released into saline.

FIG. 5 is a graph showing in vitro release of dexamethasone from 50 μLaliquots of a liquid depot formulation (10% dexamethasone, 72% vitamin Eacetate, and 18% MIGLYOL® 810 (medium chain triglycerides)), placed in200 mL saline (100 mL exchange). Six replicates were tested: y-axis, %dexamethasone released; x-axis, days; ●: GTH-83A; ◯: GTH-83B; ▪:GTH-83C; □: GTH-83D; ▪: GTH-83E; Δ: GTH-83F.

FIG. 6 is a graph showing the amount of dexamethasone detected in theanterior chamber of the eye in the days following instillation of adexamethasone-containing liquid depot. X-axis, days; y-axis,dexamethasone ng/mL (average).

FIG. 7 is a graph showing in vitro release of prednisolone from a liquiddepot formulation (10% prednisolone and 90% of a mixture of tocopherylacetate:Miglyol® 810 (medium chain triglycerides) at a wt/wt ratio ofabout 80:20) placed in 100 gm water. For each time point, 60 ml samplewas withdrawn for sampling and replaced with 60 mL saline. Sixreplicates were tested: y-axis, % prednisolone released; x-axis, days;●: GTH-64A; ◯: GTH-64B; ▪: GTH-64C; □: GTH-64D; ▴: GTH-64E; Δ: GTH-64F.

FIG. 8 is a graph showing in vitro release of prednisolone from a liquiddepot formulation (10% prednisolone and 90% of a mixture of tocopherylacetate:Miglyol® 810 (medium chain triglycerides) at a wt/wt ratio ofabout 80:20) that were placed in 100 gm water. For each time point, 50ml sample was withdrawn for sampling and replaced with 50 mL saline. Sixreplicates were tested: y-axis, % prednisolone released; x-axis, days;●: 5A; ◯: 5B; ▪: 5C; □: 5D; ▴: 5E; Δ: 5F; •: Avg.

FIG. 9 is a graph showing in vitro release of loteprednol from aloteprednol-containing liquid depot formulation (10% loteprednol and 90%of a mixture of tocopheryl acetate:Miglyol® 810 (medium chaintriglycerides) at a wt/wt ratio of about 80:20). Fifty mL of each samplewere withdrawn for sampling and replaced with 50 mL of 40%methanol/water. Two replicates were tested: y-axis, % loteprednolreleased; x-axis, days; ●: 66-A; ◯: 66-B; •: Avg.

FIG. 10 is a graph showing the amount of moxifloxacin in rabbit tearsdays after a single instillation of either 15% (♦) or 20% (▪)moxifloxacin-containing liquid depots. X-axis, days; y-axis,moxifloxacin μg/mL (average, n=6).

FIG. 11 is a graph showing the amount of moxifloxacin detected in theanterior chamber of the eye in the days following a single instillationof either 15% (♦) or 20% (▪) moxifloxacin-containing liquid depots.X-axis, days; y-axis, moxifloxacin ng/mL (average, n=6).

FIG. 12 is a graph showing in vitro release of ciprofloxacin from aciprofloxacin-containing liquid depot formulation (15% ciprofloxacin and85% of a mixture of tocopheryl acetate:Miglyol® 810 (medium chaintriglycerides) at a wt/wt ratio of about 70:30). Twenty-five mL of eachsample were withdrawn for sampling and replaced with 25 mL of saline.Six replicates were tested: y-axis, % ciprofloxacin released; x-axis,hours; ●: 24-A; ◯: 24-B; ▪: 24-C; □: 24-D; ▴: 24-E; Δ: 24-F; •: Avg.

FIG. 13 is a graph showing another in vitro release of ciprofloxacinfrom a ciprofloxacin-containing liquid depot formulation (15%ciprofloxacin and 85% of a mixture of tocopheryl acetate:Miglyol® 810(medium chain triglycerides) at a wt/wt ratio of about 70:30).Twenty-five mL of each sample were withdrawn for sampling and replacedwith 25 mL of saline. Six replicates were tested: y-axis, %ciprofloxacin released; x-axis, hours; ●: 25-A; ◯: 25-B; ▪: 25-C; □:25-D; ▴: 25-E; Δ: 25-F; •: Avg.

FIG. 14 is a graph showing in vitro release of gatifloxacin from agatifloxacin-containing liquid depot formulation (10% gatifloxacin and90% of a mixture of tocopheryl acetate:Miglyol® 810 (medium chaintriglycerides) at a wt/wt ratio of about 70:30). Twenty mL of eachsample were withdrawn for sampling and replaced with 20 mL of saline.Six replicates were tested: y-axis, % gatifloxacin released; x-axis,hours; ●: 90-A; ◯: 90-B; ▪: 90-C; □: 90-D; ▴: 90-E; Δ: 90-F; •: Avg.

FIG. 15 is a graph showing the levels of latanoprost acid in theanterior chamber following a single drop of commercially availableproduct (Xalatan® (latanoprost ophthalmic solution) 0.005%) or aone-time 50 μL instillation of one of two liquid depot latanoprostformulations. Each time point represents average of four samples takenfrom the anterior chamber of NZW rabbits (4.0-4.5 kg). y-axis:latanoprost acid pg/mL; x-axis: days following instillation; ⋄: One dropXalatan® (latanoprost ophthalmic solution) 0.005%; □: a 50 μLinstillation of 0.05% latanoprost in 80:20 EA:Miglyol® 812; Δ: a 50 μLinstillation of 0.03% latanoprost in 80:20 EA:Miglyol® 812.

FIG. 16 is a graph showing results of an in vivo PK study of diclofenacacid drug level in tear samples following instillation of a liquid depotcomprising 10% diclofenac acid in a 90% excipient mixture of 80:20tocopheryl acetate:Miglyol®. y-axis: ng diclofenac/mg tear; x-axis: day.

FIG. 17 is a graph showing in vitro release of cyclosporin from twoliquid depots containing 2% cyclosporine in an excipient mixture ofeither 90:10 tocopheryl acetate:Miglyol® 812 (♦) or 70:30 tocopherylacetate:Miglyol® 812 (▪). y-axis: cyclosporin A total release (%);x-axis: days.

DETAILED DESCRIPTION

It should be understood that this invention is not limited to theparticular methodology, protocols, and reagents, etc., described hereinand as such may vary. The terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to limit thescope of the present invention, which is defined solely by the claims.

All patents and other publications identified are incorporated herein byreference for the purpose of describing and disclosing, for example, themethodologies described in such publications that might be used inconnection with the present invention but are not to provide definitionsof terms inconsistent with those presented herein. These publicationsare provided solely for their disclosure prior to the filing date of thepresent application. Nothing in this regard should be construed as anadmission that the inventors are not entitled to antedate suchdisclosure by virtue of prior invention or for any other reason. Allstatements as to the date or representation as to the contents of thesedocuments is based on information available to the applicants and do notconstitute any admission as to the correctness of the dates or contentsof these documents.

As used herein and in the claims, the singular forms “a,” “an,” and“the” include the plural reference unless the context clearly indicatesotherwise. Throughout this specification, unless otherwise indicated,“comprise,” “comprises” and “comprising” are used inclusively ratherthan exclusively, so that a stated integer or group of integers mayinclude one or more other non-stated integers or groups of integers. Theterm “or” is inclusive unless modified, for example, by “either.” Thus,unless context indicates otherwise, the word “or” means any one memberof a particular list and also includes any combination of members ofthat list. Other than in the operating examples, or where otherwiseindicated, all numbers expressing quantities of ingredients or reactionconditions used herein should be understood as modified in all instancesby the term “about” which generally allows variation of ±1 unlesscontext dictates otherwise. In general, and unless otherwise indicatedor clarified by context, amounts or levels presented as “%” are based onweight (i.e., wt % or wt/wt).

Headings are provided for convenience only and are not to be construedto limit the invention in any way. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning asthose commonly understood to one of ordinary skill in the art. Theterminology used herein is for the purpose of describing particularembodiments only and is not intended to limit the scope of the presentinvention, which is defined solely by the claims. In order that thepresent disclosure can be more readily understood, certain terms arefirst defined. Additional definitions are set forth throughout thedetailed description.

Ophthalmic formulations are needed for delivery of pharmaceutical agentson the eye, into the eye, or onto the conjunctiva of the eye. Currentlyavailable formulations used in ophthalmology include aqueous solutions,aqueous suspensions, ointments, and inserts. In current eye dropformulations, however, transcorneal transport (i.e., drug penetrationinto the eye) is not an effective process, as an estimated one-tenth ofa dose penetrates into the eye. Moreover, current commercially availableeye drops do not provide sustained release over extended periods oftime, e.g., over the course of days. Accordingly, topical formulationsthat can effectively deliver pharmaceutical agents into tissues andfluids in the front of the eye clearly represent a long-felt but unmetneed in the art.

More specifically, current commercially available ophthalmic solutionsare aqueous based, and placed into the eye as eye drops. Currentcommercial solutions typically require instillation several times a day.Commercial ophthalmic aqueous eye drops require careful control of pH,buffer capacity, viscosity, and tonicity (osmotic pressure);particularly to avoid stinging upon application, which can lead topatient noncompliance. Current commercially available ophthalmicsuspensions are also aqueous formulations but contain solid particlesand typically produce a slightly longer effect than do solutions, butstill require administration on a daily basis. Particle size is kept toa minimum to prevent irritation of the eye, but current aqueoussuspensions are disadvantageous because of difficulty in avoidingparticles large enough to irritate the eye; and these suspensions oftencloud vision for an extended period of time after instillation. Currentophthalmic ointments are relatively difficult to apply and maydistribute unevenly in the eye. Ointments remain in contact with the eyefor an extended period compared with solutions or suspensions, producinga therapeutic effect of relatively longer duration, but this period istypically measured in hours, not days. Most ointments tend to blurpatient vision as they remain viscous and are not removed easily by thetear fluid, which is a major disadvantage: ointments leave a film overthe patient's eye that impairs the patient's vision for at least sometime. Thus, ointments are generally used at night as adjunctive therapyto eye drops used during the day.

Ophthalmic solutions usually do not impair or interfere with vision(although initial instillation may yield fleeting blurry vision), butpatients must forgo contact lenses and eye makeup whether using currentsolutions, suspensions, or ointments, and these factors also add topatient noncompliance with dosage regimen.

In addition to the considerations discussed above, ophthalmic productsmust remain sterile to prevent microbial contamination of the eye.Whether current ocular therapies are formulated as solution, suspension,or ointment, most current formulations are administered from droppers ortubes that must be used with care to avoid allowing the tip of thedropper or tube to touch the eyelid or any other surface that cancontaminate the dispenser. Contamination of a dropper, solution,suspension, or the tip or cap of the tube can lead to serious eyeinfection. Accordingly, FDA Advisory Review Panel on OTC Ophthalmic DrugProducts (1979) established preservatives and concentrations for use informulations that will have direct contact with the eye. Many of thesepreservatives react with active agents or plastics, however, or increaseirritation of the eye drops formulation.

In contrast to current commercially available ophthalmic formulations,the present embodiments provide a liquid depot that forms a film overthe eye that is not blinked away and does not impair vision exceptfleetingly at the time of administration. The present embodimentsprovide a sustained-release liquid depot that can releasespharmaceutical agent(s) such that these agents can be detected for atleast about 24 hours, at least about 36 hours, at least about 48 hours,at least about 60 hours, at least about 72 hours, at least about 7 days,at least about 14 days, or at least about 21 days, including intervalstherebetween. It is unexpected, and indeed remarkable, that the activeagent remains present in high enough concentrations to betherapeutically efficacious over the course of delivery. As shown in theExamples herein, after only a single application of liquid depot,pharmaceutical agent was detected in the tear film for at least 7 daysand the liquid depot likely released drug for at least that long.Further, without being bound by theory, because the present depotdelivers active agent to ocular tissues, some ocular tissues may becomerepositories from which drug is subsequently released, prolongingrelease or therapeutic benefit. Additionally, the liquid depot has aphysical consistency that avoids running (compared with current aqueousdrops) and allows the patient to wear contact lenses and eye makeup.

The present embodiments also advantageously provide instillation from asingle-use dispenser such that preservative is not required in theformulation; because the present liquid depot provides sustained releaseand therapeutic benefit for at least 3 days, the liquid depot can besupplied in a single-administration dispenser that is easy to usebecause the patient (or health care provider) can focus all theirattention to dispensing the formulation into the eye without divertingattention to avoiding all contact with the tip of the dispenser.Accordingly, at least one embodiment provides a single-use dispensercomprising the sustained-release liquid depot described herein, in whichthe dispenser is configured to deliver into an eye a single dose/dosageform of the liquid depot.

Additionally, oxygen sensitivity of many pharmaceutical agents resultsin instability. For this reason, current eye drops often includepreservatives, such as sodium bisulfate, to increase stability of suchactive agents. The sustained-release liquid depot described herein iscapable of releasing the active agent, at therapeutic levels, for atleast about 24 hours, more preferably at least about 48 hours, and stillmore preferably at least about 72 hours, even though the depot isexposed to oxygen from atmospheric exposure and constant washing fromfluids in the eye. It is unexpected that an active agent remains stableover the course of delivery, e.g., for at least 3 days. Without beingbound by theory, this is likely due to the antioxidant nature of thetocopherol or tocotrienol excipient, which in the present embodiments isnot unduly diluted or reduced by the presence of ocular film-formingexcipient(s). Accordingly, in at least one embodiment, thesustained-release liquid depot comprises a biocompatible andbiodegradable mixture of tocopherol or tocotrienol and an ocularfilm-forming excipient that has low solubility in aqueous solution.

In at least one embodiment, the sustained-release liquid depotcomprises: about 60% to 90% (wt %) tocopherol (such as tocopherylacetate), and about 10% to 40% (wt %) of an ocular film-formingexcipient (such as decanoyl/octanoyl glycerides). In at least oneembodiment, the liquid film-former excipient modulates (e.g., eitherincreases or decreases) the viscosity of the liquid depot. In at leastone embodiment, a liquid depot includes about 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or about 90% (wt%), inclusive, or any interval therebetween, of tocopherol; and includesabout 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%,37%, 38%, 39%, or about 40% (wt %), inclusive, or any intervaltherebetween, of ocular film-forming excipient. In one embodiment, theliquid depot comprises, consists, or consists essentially of (a) 10%-15%dexamethasone in (b) about 85%-90% (wt %) of a mixture of tocopherylacetate:medium-chain triglycerides at a weight ratio of about 90:10 toabout 60:40.

Regarding viscosity, this characteristic describes the resistance todeformation exhibited between molecules moving in a fluid, or a form ofinternal friction that resists a fluid's flow when stress is applied.The viscosity of a solution is often given in poise (P), centipoise(cP), or millipascal seconds (mPa s). For example, at 20° C. water has aviscosity of 1.00 mPa s, or 1.00 cP, whereas motor oil (SAE 40) has aviscosity of 319 mPa s. Many fluids exhibit less viscosity when heated:for example, at 25° C., water has a viscosity of 0.890 mPa s. See, e.g.,Elert, PHYSICS HYPERTEXTBOOK (1998-2017). Generally, currentaqueous-based eye drop solutions have viscosity ranging from 25 cP to 50cP (at 20° C.); and some of these ophthalmic solutions may includeviscosity enhancers added to increase viscosity and perhaps enable thesolution to remain longer in the eye. Typical compounds added to enhanceviscosity in current eye drops are available in various grades such as15 cP, 100 cP, etc., and include methylcellulose, hydroxycellulose,hydroxypropylmethyl-cellulose, polyvinyl alcohol, andpolyvinylpyrrolidone. In preferred embodiments, none of theseviscous-enhancing compounds are included in the liquid depot describedherein.

In one embodiment, a sustained-release liquid depot according to thesubject invention consists of tocopheryl acetate, MIGLYOL®, anddexamethasone having a viscosity of 850 cP to 1100 cP, such as about850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 899, 990, 994,995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007,1007, 1008, 1009, 1010, 1011, 1020, 1021, 1022, 1023, 1024, 1025, 1026,1027, 1028, 1029, 1030, 1031, 1032, 1075, 1076, 1077, 1078, 1079, 1080,1081, 1082, 1083, 1099, or 1100 cP, inclusive of any cP therebetween. Inanother embodiment, a sustained-release liquid depot, according to thesubject invention, consists of tocopheryl acetate, MIGLYOL®, anddexamethasone having a viscosity of about 1027 cP. In anotherembodiment, a sustained-release liquid depot, according to the subjectinvention, consists of tocopheryl acetate, MIGLYOL®, and dexamethasonehaving a viscosity of 1027 cP±32 cP.

In at least one embodiment, the sustained-release liquid depotcomprises, consists of, or consists essentially of a tocopherol and anocular film-forming excipient. As used herein, “tocopherol” includestocopherols, tocotrienols, esters thereof, and mixtures thereof.Tocopherol is commonly known as “vitamin E.” Tocopherols andtocotrienols contain a chromanol ring and a hydrophobic side-chain ofsixteen carbons. Depending on the pattern of methylation of thechromanol ring, these compounds exist as α-, β-, γ- and δ-tocopherols,each with a saturated side chain; or as α-, β-, γ- and δ-tocotrienols,each with a side chain containing three double bonds in the side chain.Tocopherols and tocotrienols can be extracted from a number of plantsources, such as palm oil. See, e.g., WO2014100327; Lee et al., Methodsfor efficient analysis of tocopherols, tocotrienols & their metabolitesin animal samples with HPLC-EC, J. Food Drug Anal. 1-12 (2017). Thetocopherol component of the present embodiments remains in liquid formin the depot and does not undergo phase shift to solid, crystalline, orliquid crystalline form upon contact with water or aqueous bodilyfluids, e.g., tears. Tocopherols are highly viscous liquids, and theirability to flow at different conditions related to temperature and flowvelocity is a fundamental property of tocopherols. The term “tocopherol”may be used herein to denote any of these liquid tocopherols ortocotrienols and derivatives thereof as provided herein and suitable foruse as described herein.

In at least one embodiment, the tocopherol is tocopheryl acetate (alsoknown as tocopherol acetate, vitamin E acetate, or “EA”), an ester oftocopherol and acetic acid. More specifically, tocopheryl acetate, IUPACname“[(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-yl]acetate” (CAS Reg. No. 58-95-7), has low solubility in aqueous solution(having water solubility of <0.1 g/100 mL at 17° C.), a viscosity of6.31 Pa s to 6.59 Pa s (20° C.), and a refractive index of 1.496 n20/D.By comparison, the average refractive index values of human tears areabout 1.33698. Craig et al., Refractive index & osmolality of humantears, 72(10) Optom. Vis. Sci. 718-24 (1995). In one embodiment, thetocopherol is tocopheryl acetate. In at least one embodiment, the liquiddepot comprises any amount from 60% to 90%, inclusive, such as 60%, 61%,62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or90% (wt %), tocopheryl acetate.

In addition to a tocopherol, the sustained-release liquid depotdescribed herein includes an additional ocular film-former excipient,which in general terms is an excipient that is biocompatible and safe touse in the human eye, has low solubility in aqueous solution, does notimpair vision (e.g., has a suitable refractive index at least incombination with tocopherol), and does not adversely affect eithertocopherol stability in the eye or release of the pharmaceuticalagent(s) from the liquid depot. It should be understood that althoughtocopherol is generally capable of forming a film in the eye andproviding sustained release, tocopherol is too viscous for practical usein the liquid depot described herein; the ocular film-forming excipientimproves the spreadability or hastens the application of the liquiddepot described herein. In general, the ocular film-forming excipientrenders the tocopherol less viscous. In other words, compared withtocopherol (e.g., tocopheryl acetate) as the sole component of a liquiddepot, the additional ocular film-forming component provides a liquiddepot that is comparatively less sticky, tacky, or viscous. This ocularfilm-forming excipient facilitates rapid and smooth coverage over thecornea, and also modifies the viscosity of the tocopherol component(e.g., tocopheryl acetate). It should be noted, however, that inclusionof too much film-forming agent results in insufficient film depot andincreases flushing of the active agent(s) from the eye.

Generally speaking, the ratio of tocopherol:film-forming excipient(e.g., wt/wt ratio) can be adjusted to modulate (e.g. either increase ordecrease) the sustained release profile of the liquid depot. Forexample, decreasing the amount of film-forming excipient generallyincreases the time in which the liquid depot stays in the eye anddelivers active agent(s), i.e., increases the sustained release profile.Alternatively, or additionally, depending on the indication, thesustained release profile can be extended by increasing the amount ofactive agent(s) in the liquid depot. Further, depending on theindication, the concentration of active agent can be increased toincrease the amount of active agent that is delivered to the front ofthe eye, e.g., the cornea, by the liquid depot.

Use of particular ocular film-forming excipients and the amount of eachadditional ocular film-former included in the sustained-release liquiddepot described herein has been determined through laborious anddetailed experiments to provide the type of excipient with the requiredcharacteristics and the amount needed to provide non-stick, nearlyimmediate coating over the cornea with sufficient tocopherol to providesustained release of pharmaceutical agent from the liquid depot. Therequired beneficial characteristics of the ocular film-forming excipientinclude safety for use in the eye, chemical and physical stability overa long period of time, chemical compatibility with other formulationcomponents, solubility in the formulation, ability to enhance thesustained release of the pharmaceutically active component, inertness,and the diffusion away from the liquid depot after exerting the desiredeffects.

Many potential film-forming excipients were considered or evaluated forinclusion in the liquid depot of the present embodiments, includingcastor oil, corn oil, triacetin, tributyrin, tricaprin, tricaprylin,water, Dermol esters (e.g., isononyl isononanoate), BENZOFLEX™(plasticizer), polyethylene and polypropylene glycols, long chainaliphatic alcohols, hydroxypropyl methyl cellulose (HPMC), stearicacids, and stearic esters. These carriers were found to lack at leastone of the multiple beneficial characteristics needed in order toprogress through the rigorous evaluation processes employed to arrive atthe liquid depot described herein. These excipients are not included inthe liquid depot described herein.

In at least one embodiment, the ocular film-forming excipient is amixture of triglycerides. In at least one embodiment, the ocularfilm-forming excipient is one or more medium-chain triglycerides (MCT).For example, mixed decanoyl and octanoyl glycerides (e.g., CAS No.73398-61-5), comprise >95% saturated fatty acid chains, and aretransparent, colorless or slightly yellow liquids, immiscible in water,practically odorless and tasteless, specific gravity of 0.94-0.96 (20°C.), refractive index of 1.440 to 1.452 n20D (20° C.), and viscosityranging from 24 mPa s to 33 mPa s (20° C.) (14.9 cSt at 100° C.).Synonyms for MCT include ecanoyl/octanoyl glycerides, mixed decanoateand octanoate triglycerides, glyceryl tricaprylate/caprate, oleumneutrale, Bergabest, Captex® 300, Captex® 355, Crodamol® GTCC/C,Labrafac® CC, MCT oil, MIGLYOL® 810, MIGLYOL® 812, Myritol®, Neobee® M5,Nesatol®, or Waglinol® 3/9280. Accordingly, film-formers may also bereferred to as triglycerides (and triglyceride-like) excipients, thatinclude decanoyl/octanoyl glycerides (such as MIGLYOL® 810),caprylic/capric triglyceride (e.g., MIGLYOL® 812), and propylene glycoldicaprylate/dicaprate (triglyceride like) (e.g., MIGLYOL® 840), andmixtures thereof.

In exemplary embodiments, MIGLYOL®, when combined with tocopherol,imparts beneficial sustained release characteristics to the liquid depotdescribed herein: such as beneficial modulation of viscosity,flowability, inertness, transparency, solubility with other components,and permeability.

Accordingly, in one embodiment, the film-forming excipient is immiscibleor has low solubility in water or aqueous solution. In one embodiment,the film-forming excipient has a viscosity of 27 mPa s to 33 mPa s (20°C.), inclusive, such as about 27, 28, 29, 30, 31, 32, or about 33 mPa s(20° C.), including intervals therebetween. In one embodiment, thefilm-forming excipient has a refractive index of 1.448 n20D to 1.451n20D, such as about 1.448, 1.449, 1.450, or about 1.451 n20D, orintervals therebetween. In one embodiment, the film-forming excipientcomprises, consists of, or consists essentially of decanoyl/octanoylglycerides. In one embodiment, the decanoyl/octanoyl glyceridesexcipient is at least one of MIGLYOL® 810 or MIGLYOL® 812. In at leastone embodiment, the liquid depot includes any amount from 10% to 30%,inclusive, decanoyl/octanoyl glycerides, such as MIGLYOL® 810 orMIGLYOL® 812.

The liquid depot, when lacking a pharmaceutical agent (i.e., before anagent is loaded into the depot) may also be referred to as a blank,control, excipient component of a formulation, biodegradable excipient,excipient mixture, vehicle, and the like. The liquid depot remains inliquid state under physiologic conditions, both in vitro and in vivo,and does not polymerize or become solid after placement in the eye. Thisliquid depot can be loaded with highly concentrated active agent, butnevertheless remains liquid, safe and effective, while reducing sideeffects normally associated with the active agent administered intraditional eye drop formulations. Loading refers to any means by whichat least one active agent is dispersed, dissolved, mixed, suspended, orotherwise incorporated into the liquid depot. Liquid refers generally tofluids, but also includes suspensions of solids dispersed in liquids(dispersions, suspensions, colloidal mixtures), and gasses dissolved inor otherwise present together within liquids, wherein fluidity of theliquid is maintained. The liquid depot of the present embodimentsretains its fluid nature (i.e., does not solidify) before and afterplacement in the eye, and remains fluid as it biodegrades over time. Inat least one embodiment, the liquid depot does not contain apharmaceutical agent, and when instilled into the eye provides a liquid“bandage” or eye band aid useful for a variety of maladies includinginflammation or eye protection.

In at least one embodiment, a single administration of the liquid depot,such as instillation of a liquid depot of about 20 μm³ (20 μL) to about70 μm³ (70 μL) (such as about 20 μL, 25 μL, 30 μL, 35 μL, 40 μL, 45 μL,50 μL, 55 μL, 60 μL, 65 μL, or about 70 μL, including intervalstherebetween) provides for sustained release of a pharmaceutical agentto an interior tissue of the eye for at least about 24 hours, at leastabout 48 hours, at least about 72 hours, at least about 4 days, at leastabout 5 days, at least about 6 days, at least about 1 week (7 days), atleast about 2 weeks (14 days), or at least about 3 weeks (21 days),including intervals therebetween. In at least one embodiment, a singleinstillation of the liquid depot, such as a liquid depot of about 20 μm³(20 μL) to about 70 μm³ (70 μL), inclusive and including intervalstherebetween, provides for sustained release of active agent to aninterior tissue of the eye for a period of at least about 24 hours, atleast about 48 hours, at least about 72 hours, at least about 4 days, atleast about 7 days (1 week), at least about 2 weeks, or at least about 3weeks, including intervals therebetween. It should further be understoodthat a single instillation might include two micro-drops (e.g., of 25μL) instilled in rapid succession to provide a single one-time dose(e.g., of 50 μL).

Many pharmaceutical agents are suitable for sustained release from theliquid depot described herein. Such agents may have low solubility inwater or aqueous solutions. In some embodiments, active agents are morestable in the liquid depot compared with the stability of those activeagents in current aqueous-based eye drop formulations.

It should be noted that, without being bound by theory, it appears thatthe efficiency with which the liquid depot delivers active agents toocular tissues allows some tissues to retain agents after the depot filmhas dissipated, extending release from such tissues or benefit to suchtissues after the liquid depot is gone.

References to “pharmaceutical agent,” “pharmaceutically active,”“pharmaceutical,” “drug,” “medicament,” “active agent,” “active drug,”“bioactive agent” or “therapeutic agent” and the like, refer in ageneral sense to substances useful in the medical and scientific arts,including, for example, drugs, biologics, diagnostic agents (e.g, dyesor contrast agents) or other substances used for therapeutic,preventative, diagnostic, or research purposes. Example pharmaceuticalagents include biologics (e.g., insulin), chemotherapeutic agents, smallmolecules, antigens, interferons, polyclonal or monoclonal antibodies,anesthetics, interfering RNAs, gene vectors, contrast agents, orcombinations of any of these. Reference to general or specificpharmaceutical agents or drugs includes pharmaceutically acceptableanalogues, derivative, and salts thereof. For example, reference toketotifen includes ketotifen fumarate. Active agents that may beincluded in the liquid depots described herein are provided, forexample, in U.S. Pat. No. 9,011,915.

“Inactive” substances typically refer to carriers, excipients, diluents,and the like, which are well-known in the art, although such substancesmay have beneficial function, such as, for example, stabilizing apharmaceutical agent.

Typically, pharmaceutical agents are administered to the eye to haverelatively local effects such as miosis, mydriasis, and anesthesia, orto reduce intraocular pressure (IOP) in treating glaucoma. Without beingbound by theory, because the liquid depot formulations described hereindeliver active agents to ocular tissues, in some instances such oculartissues retain active agent after the depot is no longer evident in thetear film, further providing sustained release of the active agent.

In at least one embodiment, an active agent is delivered to the eye in amanner that provides treatment or prevention (e.g., prophylaxis) ofocular disease in the front of the eye. In some embodiments, the frontof the eye is the surface of the eye. In some embodiments, the front ofthe eye includes the ocular tissue and fluids in the front of the eyeincluding aqueous humor, cornea, conjunctiva, and iris/ciliary body.Regarding the surface of the eye, the present embodiments provide fortreatment or prevention of maladies associated with the surface of theeye, including conjunctivitis, allergy, acute dry eye, dry eye,irritation, or infection. In some embodiments, delivery of the activeagent from the sustained-release liquid depot provided herein isintermittent, e.g., once every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days,once every 2 weeks, or once every 3 weeks.

In one embodiment, an active agent is delivered to the eye in a mannerthat provides treatment or prevention (e.g., prophylaxis) of oculardisease in the front of the eye (anterior), while, optionally,concurrently treating or preventing ocular disease in the back of theeye (posterior).

In at least one embodiment, one application of the sustained-releaseliquid depot delivers active agent(s) to the front of the eye for atleast 3 days. In at least one embodiment, one application of thesustained-release liquid depot delivers active agent(s) to the front ofeye for at least 7 days. In at least one embodiment, one application ofthe sustained-release liquid depot delivers active agent(s) to the frontof eye for at least 14 days.

In another aspect, methods of managing a clinical condition associatedwith or affecting front of the eye are provided, comprising theintermittent administration (e.g., once every 3, 4, 5, 6, 7, 8, 9 or 10days, once every 2 weeks, or once every 3 weeks) of a single dose of amedicament-containing liquid depot as described herein, wherein the doseis about 20 μL to about 70 μL, inclusive and including volumestherebetween. It should be understood that reference to intermittentdosage regimens reflects therapeutic dose over an extended period oftime, such that administering once every three days or longer impliesthat sustained release has provided therapeutic effect such that morefrequent administration is not indicated.

In one embodiment, the clinical condition is inflammation. In oneembodiment, the clinical condition is allergy. In one embodiment, theclinical condition is infection. In one embodiment, the clinicalcondition is intraocular pressure or glaucoma. In one embodiment, theclinical condition is uveitis. It should be understood, however, thatthese indications may not be mutually exclusive; for example, infectionis often associated with inflammation. Similarly, anti-infectives suchas cyclosporine, are often administered to reduce inflammation.Accordingly, at least one embodiment provides a liquid depot formulationfor prophylaxis of infection and inflammation, such as, for example,blepharitis, or inflammatory meibomian gland disease.

Another aspect of the present embodiments provides a method of treatinga disease or malady of the eye, such as infection, corneal abrasion orother trauma to the eye surface, blepharitis, inflammatory meibomiangland disease, meibomian gland dysfunction, allergic conjunctivitis,chronic conjunctivitis, Sjögren's syndrome, dry eye(keratoconjunctivitis sicca), aqueous-deficient dry eye, mucin-deficientdry eye (punctate epithelial keratitis), episcleritis, keratitis(corneal ulcers), pterigia, Stevens-Johnson syndrome, ocular citatricalpemphigoid/mucous membrane pemphigoid, irregular cornea condition orother surface abnormalities, epitheliopathy, neurotrophic cornea,corneal dystrophy such as Fuch's dystrophy, peripheral or marginaldegeneration of the cornea, conjunctivochalasis, glaucoma, conjunctivaldegeneration such as pinguecula, pingueculitis, or re-epithelializationof corneal epithelial defects in patients who have undergonephotorefractive keratectomy.

In some embodiments, the sustained-release liquid depot comprises, asthe pharmaceutical agent, a bioactive or therapeutic agent. Bioactive ortherapeutic agents may have more than one activity or benefit, hence thefollowing embodiments are not mutually exclusive. For example,anti-inflammatory steroids may have angiostatic activity as well. Insome embodiments, the sustained-release liquid depot comprises at leastone anti-inflammatory agent. In some embodiments, the sustained-releaseliquid depot comprises at least one anti-allergy agent. In someembodiments, the sustained-release liquid depot comprises at least oneanti-infective. In some embodiments, the sustained-release liquid depotcomprises at least one anti-glaucoma therapy.

In another embodiment, the sustained-release liquid depot contains twoor more different active agents, wherein each active agent selected forits ability to either stay associated with the cornea or pass throughthe cornea, such that one active agent stays on or in the cornea and theother active agent penetrates the interior of the eye. In oneembodiment, the liquid depot includes two or more active agents withsimilar capacities to penetrate the eye.

At least one embodiment provides a liquid depot that releasesanti-allergy therapy, such as antihistamine or mast cell stabilizer.Exemplary anti-allergy agents used to treat allergies/itchy eyesinclude, for example, ketotifen, ketotifen fumarate, lodoxamine,azelastine, olopatadine, or epinastine, or combinations thereof.

Accordingly, a specific embodiment is a liquid depot comprisingtocopherol, ocular film-forming excipient, and ketotifen. An exemplaryembodiment includes about 70% to 80% (wt %) tocopherol (such astocopheryl acetate), about 10% to 30% (wt %) ocular film-formingexcipient, such as decanoyl/octanoyl glycerides (e.g., MIGLYOL®), andketotifen.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming excipient, and lodoxamine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and lodoxamine.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and azelastine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and azelastine.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming excipient, and olopatadine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and olopatadine.

Yet another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming excipient, and epinastine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and epinastine.

At least one embodiment provides a liquid depot that releasesanti-glaucoma therapy. Anti-glaucoma active agents includeinflow-suppressing/inhibiting agents, such as beta blocking agents(e.g., timolol, betaxolol, carteolol, levobunolol, etc.), topicalcarbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide),sympathomimetics (e.g., epinephrine, dipivefrin, clonidine,apraclonidine, brimonidine), outflow-facilitating agents includingparasympathomimetics (e.g., cholinergic agonists such as pilocarpine),and prostaglandin analogues and related compounds (e.g., latanoprost,travoprost, bimatoprost, unoprostone, or tafluprost). Differentpharmaceutical agents can be used alone or in combination to reduceintraocular pressure, including, for example, bimatoprost, latanoprost,travaprost, tafluprost, brimonidine, betaxolol, levobunolol,metipranolol, or timolol.

Accordingly, a specific embodiment is a liquid depot comprisingtocopherol, ocular film-forming excipient, and timolol. An exemplaryembodiment includes about 70% to 80% (wt %) tocopherol (such astocopheryl acetate), about 10% to 30% (wt %) ocular film-formingexcipient, such as decanoyl/octanoyl glycerides (e.g., MIGLYOL®), andtimolol.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and betaxolol. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and betaxolol.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and carteolol. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and carteolol.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and levobunolol. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and levobunolol.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and dorzolamide. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and dorzolamide.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and brinzolamide. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and brinzolamide.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and epinephrine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and epinephrine.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and dipivefrin. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and dipivefrin.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and clonidine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®) and clonidine.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and apraclonidine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and apraclonidine.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and brimonidine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and brimonidine.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and pilocarpine. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and pilocarpine.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and latanoprost. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and latanoprost.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and travoprost. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and travoprost.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and bimatoprost. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and bimatoprost.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and unoprostone. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and unoprostone.

Yet another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and tafluprost. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and tafluprost.

At least one embodiment provides a sustained-release liquid depot thatreleases anti-inflammatory therapy, such as nonsteroidalanti-inflammatory drugs (NSAIDs), or steroidal anti-inflammatory, e.g.,corticosteroids. The embodiments described herein support use of theliquid depot for a breadth of clinical indications for whichanti-inflammatories are used. For example, although true anti-histaminesare often used as anti-allergy eye drops, anti-inflammatories,including, e.g., loteprednol, are also used to alleviate allergies. Forexample, corticosteroids are used to treat allergic conjunctivitis.Indeed, the sustained-release liquid depot formulations comprisinganti-inflammatory medicines as described herein may find clinicalapplication in many different clinical indications, e.g., in treating orpreventing: (a) conjunctivitis, (b) dry eye, (c) inflammation associatedwith ocular surgery, including but not limited to, cataract surgery andvitrectomy, (d) allergy, (e) itchy eyes, (f) uveitis, (g) blepharitis,or (h) inflammatory meibomian gland disease.

Accordingly, at least one embodiment provides a method of treatingocular inflammation comprising instilling into the eye of a patient inneed thereof a sustained-release liquid depot comprising, consisting, orconsisting essentially of anti-inflammatory agent, tocopherol, and MCT(decanoyl/octanoyl glycerides). In some embodiments, theanti-inflammatory agent is a corticosteroid, the tocopherol istocopheryl acetate, and the MCT is MIGLYOL®. In a particular embodiment,the liquid depot consists of 10% (wt %) dexamethasone, 72% (wt %)tocopheryl acetate, and 18% (wt %) MIGLYOL®, and dexamethasone isreleased for at least 7 days.

At least one embodiment provides a method of treating ocular infectioncomprising instilling into the eye of a patient in need thereof asustained-release liquid depot comprising, consisting, or consistingessentially of anti-infective agent, tocopherol, and MCT(decanoyl/octanoyl glycerides). In some embodiments, the anti-infectiveagent is a quinolone antibiotic, the tocopherol is tocopheryl acetate,and the MCT is MIGLYOL®. In a particular embodiment, the liquid depotconsists of 15% (wt %) moxifloxacin suspended, mixed, or dissolved in85% (wt %) of a mixture of 70% (wt %) tocopheryl acetate and 30% (wt %)MIGLYOL®, and moxifloxacin is released for at least 7 days. In aparticular embodiment, the liquid depot consists of 20% (wt %)moxifloxacin suspended, mixed, or dissolved in 80% (wt %) of a mixtureof 70% (wt %) tocopheryl acetate and 30% (wt %) MIGLYOL®, andmoxifloxacin is released for at least 7 days.

In at least one embodiment, the liquid depot includes a corticosteroidanti-inflammatory, such as, for example, dexamethasone, prednisolone,prednisone, loteprednol, triamcinolone, or fluorometholone orcombinations thereof. Other anti-inflammatory agents are known in theart.

Accordingly, a specific embodiment is a liquid depot comprisingtocopherol, ocular film-forming agent, and dexamethasone. An exemplaryembodiment includes about 70% to 80% (wt %) tocopherol (such astocopheryl acetate), about 10% to 30% (wt %) ocular film-formingexcipient, such as decanoyl/octanoyl glycerides (e.g., MIGLYOL®), anddexamethasone.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and prednisolone. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and prednisolone.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and prednisone. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and prednisone.

Another specific embodiment is a liquid depot comprising tocopherol,ocular film-forming agent, and loteprednol. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and loteprednol.

Accordingly, a specific embodiment is a liquid depot comprisingtocopherol, ocular film-forming agent, and fluorometholone. An exemplaryembodiment includes about 70% to 80% (wt %) tocopherol (such astocopheryl acetate), about 10% to 30% (wt %) ocular film-formingexcipient, such as decanoyl/octanoyl glycerides (e.g., MIGLYOL®), andfluorometholone.

As noted above, anti-infectives such as cyclosporine are oftenadministered to reduce inflammation. Accordingly, in at leas oneembodiment, the liquid depot comprises cyclosporine. An exemplaryembodiment includes about 70% to 80% (wt %) tocopherol (such astocopheryl acetate), about 10% to 30% (wt %) ocular film-formingexcipient, such as decanoyl/octanoyl glycerides (e.g., MIGLYOL®), andcyclosporine.

In at least one embodiment, the liquid depot comprises a non-steroidalanti-inflammatory agent (NSAID), such as, for example, ketorolac,nepafenac, bromfenac, or diclofenac, or combinations thereof.

Accordingly, in one embodiment, the liquid depot contains tocopherol,ocular film-forming excipient, and ketorolac. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and ketorolac.

In one embodiment, the liquid depot contains tocopherol, ocularfilm-forming agent, and nepafenac. An exemplary embodiment includesabout 70% to 80% (wt %) tocopherol (such as tocopheryl acetate), about10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and nepafenac.

In another embodiment, the liquid depot contains tocopherol, ocularfilm-forming agent, and bromfenac. An exemplary embodiment includesabout 70% to 80% (wt %) tocopherol (such as tocopheryl acetate), about10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and bromfenac.

In yet another embodiment, the liquid depot contains tocopherol, ocularfilm-forming agent, and diclofenac. An exemplary embodiment includesabout 70% to 80% (wt %) tocopherol (such as tocopheryl acetate), about10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and diclofenac.

At least one embodiment provides a liquid depot for the sustainedrelease of anti-infectives useful in treating or preventing topicalocular or intraocular infections. In at least one embodiment, the liquiddepot comprises an anti-infective such as, for example, moxifloxacin,gatifloxacin, levofloxacin, ciprofloxacin, gentamicin, tobramycin, orchloramphenicol, or combinations thereof.

Accordingly, in one embodiment, the liquid depot contains tocopherol,ocular film-forming excipient, and moxifloxacin. An exemplary embodimentcontains 10%-30% (wt %) moxifloxacin in 70%-90% (wt %) of a mixture of65%-90% (wt %), tocopherol (such as tocopheryl acetate) and 10%-35% (wt%) ocular film-forming excipient, such as decanoyl/octanoyl glycerides(e.g., MIGLYOL®). In other words, an embodiment of a moxifloxacin liquiddepot for the sustained release of moxifloxacin contains 10%-30% (wt %)moxifloxacin, 58.5%-81% tocopherol, and 9%-31.5% film-forming excipient.In another embodiment, the liquid depot contains 15%-20% (wt %)moxifloxacin in 80%-85% (wt %) of a mixture of 65%-90% (wt %),tocopherol (such as tocopheryl acetate) and 10%-35% (wt %) ocularfilm-forming excipient, such as decanoyl/octanoyl glycerides (e.g.,MIGLYOL®).

In one embodiment, the liquid depot contains tocopherol, ocularfilm-forming agent, and gatifloxacin. An exemplary embodiment includes10%-30% (wt %) gatifloxacin in 70%-90% (wt %) of a mixture of 65%-90%(wt %) tocopherol (such as tocopheryl acetate) and 10%-35% (wt %) ocularfilm-forming excipient, such as decanoyl/octanoyl glycerides (e.g.,MIGLYOL®).

In one embodiment, the liquid depot contains tocopherol, ocularfilm-forming excipient, and levofloxacin. An exemplary embodimentcontains levofloxacin in 70%-90% (wt %) of a mixture of about 65% toabout 90% (wt %), inclusive, tocopherol (such as tocopheryl acetate),and about 10% to about 35% (wt %), inclusive, ocular film-formingexcipient, such as decanoyl/octanoyl glycerides (e.g., MIGLYOL®).

In one embodiment, the liquid depot contains tocopherol, ocularfilm-forming agent, and ciprofloxacin. An exemplary embodiment includesabout 70% to 80% (wt %) tocopherol (such as tocopheryl acetate), about10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and ciprofloxacin.

In another embodiment, the liquid depot contains tocopherol, ocularfilm-forming agent, and gentamycin. An exemplary embodiment includesabout 70% to 80% (wt %) tocopherol (such as tocopheryl acetate), about10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and gentamycin.

In one embodiment, the liquid depot contains tocopherol, ocularfilm-forming agent, and tobramycin. An exemplary embodiment includesabout 70% to 80% (wt %) tocopherol (such as tocopheryl acetate), about10% to 30% (wt %) ocular film-forming excipient, such asdecanoyl/octanoyl glycerides (e.g., MIGLYOL®), and tobramycin.

In yet another embodiment, the liquid depot contains tocopherol, ocularfilm-forming agent, and chloramphenicol. An exemplary embodimentincludes about 70% to 80% (wt %) tocopherol (such as tocopherylacetate), about 10% to 30% (wt %) ocular film-forming agent, such asfatty acid ester(s) (e.g., decanoyl/octanoyl glycerides), andchloramphenicol.

At least one embodiment provides a liquid depot formulation forprophylaxis of infection and inflammation, such as cystoid macular edema(CME) or uveitis (both of which may be associated with cataractsurgery), blepharitis, and Inflammatory Meibomian Gland Disease.

Regarding uveitis, the uvea is the middle layer of the eye that containsmuch of the eye's blood vessels in addition to the iris, ciliary body,and choroid. Uveitis is a potentially blinding inflammation of thistissue, which disrupts vision by causing problems with the lens, retina,optic nerve, and vitreous. Uveitis can be anterior, intermediate,posterior or pan-uveitis, and is typically treated with steroids toreduce inflammation. A study comparing oral corticosteroids (prednisone)with a surgically implanted sustained release corticosteroid (0.59 mgfluocinolone acetonide intra-vitreous implant) revealed that althoughboth treatments decreased inflammation in the eye, the corticosteroidimplant produced more eye problems, such as cataracts, abnormally highintraocular pressure (IOP≥21 mmHg), and glaucomatous optic nerve damage.Indeed, 69% of patients assigned to the implant required IOP loweringtherapy, versus 26% of the systemic group; 15% versus 3% had an IOPspike to at least 40 mmHg; 23% versus 6% developed glaucomatous opticnerve damage; and 32% versus 5% required a surgical intervention.Importantly, the study concluded that IOP elevations in a substantialproportion of implanted patients would not be controllable with currenteye drops therapy. Friedman et al., Risk of elevated intraocularpressure and glaucoma in patients with uveitis; results of theMulticenter Uveitis Steroid Treatment Trial, 120 (8) Ophthalmol. 1571-79(2013).

Regarding cataract, characterized by the development of lenticularopacities, cataract is a leading cause of blindness worldwide. Becauseadverse sequelae of cataract surgery include CME and uveitis, cataractsurgeons often prescribe prophylactic administration of both steroidaland non-steroidal anti-inflammatory eye drops. Non-steroidalanti-inflammatory agents are included in prophylaxis to avoid long-term,high dose exposure to corticosteroids, which can cause elevatedintraocular pressure and glaucoma as noted above. This combination isalso prescribed to expose both anterior and posterior tissues toprophylaxis. Current eye drops formulations of corticosteroidalanti-inflammatory agents, however, raise IOP at least temporarily and insome patients IOP can remain above normal.

In contrast to the IOP sequelae described above, thedexamethasone-loaded liquid depot provided herein has not resulted inclinically significant elevated IOP. This result is surprisingconsidering that current steroidal eye drops that raise IOP include only0.1% (wt) corticosteroid, while, in contrast, the embodiments describedherein can include 10% to 15% (wt %) corticosteroid (for example,dexamethasone).

In one embodiment, the sustained-release liquid depot consists of about10% dexamethasone, about 15% dexamethasone, or from 10% to 15%dexamethasone, such as about 10%, 11%, 12%, 13%, 14%, or about 15% (wt%), or any interval therebetween, in a balance of a liquid mixturecomprising, consisting of, or consisting essentially of about 70% toabout 80% tocopherol (such as about 70%, 71%, 72%, 73%, 74%, 75%, 76%,77%, 78%, 79%, or about 80% (% wt), or an interval therebetween) and 20%to 30% film-forming excipient(s) (such as about 20%, 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, or about 30% (% wt) or an intervaltherebetween). In a specific embodiment, the tocopherol is tocopherylacetate and the film-forming excipient is MIGLYOL® 810.

In one embodiment, the sustained-release liquid depot consists of about15% moxifloxacin, about 20% moxifloxacin, or from 15% to 20%moxifloxacin, such as about 15%, 16%, 17%, 18%, 19%, or about 20% (wt%), or any interval therebetween, in a balance of a liquid mixturecomprising, consisting of, or consisting essentially of about 70% toabout 80% tocopherol (such as about 70%, 71%, 72%, 73%, 74%, 75%, 76%,77%, 78%, 79%, or about 80% (% wt), or an interval therebetween) and 20%to 30% film-forming excipient(s) (such as about 20%, 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, or about 30% (% wt) or an intervaltherebetween). In a specific embodiment, the tocopherol is tocopherylacetate and the film-forming excipient is an MCT or MIGLYOL® 810 N.

Further regarding film-forming excipients, Crodamol® GTCC or Crodamol®GTCC/C are fully saturated triesters, primarily caprylic/caprictriglyceride, having a refractive index of 1.4485-1.4500 (n 20 D), lowsolubility in water, viscosity of 25-33 mPas (at 20° C.), and a relativedensity 0.93-0.96 g/cm³ (g/mL).

MIGLYOL® 818 is a triglyceride of the fractionated C₈ and C₁₀ plantfatty acids (caprylic/capric/linoleic triglyceride; contains about 4%-5%linoleic acid. Viscosity 30-35 mPa·s (20° C.); miscible in oils.

MIGLYOL® 829 (caprylic/capric/succinic triglyceride); caprylic/capricglyceride units crosslinked with succinic acid to form a larger moleculewith unique properties; a glycerin ester of the fractionated C₈ and C₁₀plant fatty acids, combined with succinic acid; viscosity is about 230mPa·s (20° C.); high density of 1.00-1.02 g/cm³ M (20° C.); virtuallynon-miscible in water.

MIGLYOL® 840, CAS #77466-09-2 is a propylene glycol diester of saturatedplant fatty acids with chain lengths of C₈ and C₁₀; majority caprylicacid, less capric acid, small amounts of caproic, lauric and myristicacids; density 0.91-0.93 g/cm³ (20° C.); viscosity 9-12 mPa s (20° C.);refractive index 1.440-1.442 n20D; miscible in oils.

Neobee® M5 is another fully saturated triester, primarilycaprylic/capric triglyceride, having a refractive index of 1.4480-1.4510(n 20 D), low solubility in water, viscosity of 25-33 mPas (20° C.), andrelative density 0.94 g/cm³ at 20° C.

Not all excipients are suitable film-forming agents for use in theembodiments described herein. For example, although cholesterol (CAS#57-88-5) has a refractive index of 1.53 n 20 D, low solubility inwater, and is used as a nonionic emulsifier, and although cholesterolhas been included with cyclodextrins or Vaseline in preparations fortreating dry eye, cholesterol was found unsuitable for use in atocopherol-based liquid depot as described herein.

Further regarding tocopherols, α-Tocopherol: refractive index (RI)1.503-1.507; practically insoluble in water; density 0.947-0.951 g/cm³;oil. Tocopherols are incompatible with peroxides and metal ions,especially iron, copper, and silver; d-Alpha tocopherol: CAS #59-02-9;oil; d-α-tocopherol is the naturally occurring form of alpha-tocopherol;d-Alpha tocopheryl acetate: CAS #58-95-7; oil; dl-Alpha tocopherylacetate: CAS 7695-91-21; RI 1.4950-1.4972; density 0.953 g/cm3, unstableto alkali, more stable than alpha-tocopherol, oil; Beta tocopherol: oil;CAS #148-03-8; Delta tocopherol: CAS #119-13-1; oil; Gamma tocopherol:CAS #7616-22-01; α-Tocotrienol: Refractive index: 1.523; β-Tocotrienol:Refractive index: 1.52, oil.

In at least one embodiment, the liquid depot does not contain apharmaceutical agent, (i.e., it comprises, consists of, or consistsessentially of tocopherol and film forming excipient), and wheninstilled into the eye the liquid depot forms a film that provides aliquid “bandage.” In one embodiment, the liquid bandage comprises,consists of, or consists essentially of tocopheryl acetate andtriglycerides. In one embodiment, the liquid bandage comprises, consistsof, or consists essentially of tocopheryl acetate and MIGLYOL® (neutraloil). In one embodiment, the liquid bandage has a viscosity of about 850cP to about 1100 cP, inclusive. This embodiment may be useful, forexample, in the re-epithelialization of larger corneal epithelialdefects in patients who have undergone photorefractive keratectomy, orfor more general prophylaxis or eye protection.

EXAMPLES Example 1. Liquid Depot

To characterize a tocopherol-based liquid depot system, a single aliquotof 50 μL of vitamin E acetate was instilled into rabbit eyes.Subsequently, tear samples were collected using filter paper strips, andthe vitamin E acetate contained in the paper strips extracted usingmethanol. The amount of vitamin E acetate in the methanol extracts wasanalyzed using LC/MS/MS by known methods. Vitamin E acetate was observedin tear samples collected on days 1, 4, 7, and 12, as shown in Table 1,and the results are shown graphically in FIG. 3.

TABLE 1 Vitamin E acetate in rabbit tear sample from MeOH extract ofpaper strips Day Ave (ng/mL) # of samples 1 5249.50 4 4 114.13 4 7 98.634 12 27.40 6

Additionally, at days 1, 4, 7, and 12, aqueous humor samples werecollected from four eyes using syringes, then analyzed for the amount ofvitamin E acetate in each sample using LC/MS/MC (quantification limit1.0 ng/mL). No detectable vitamin E acetate was observed in aqueoushumor samples on days 1, 4, 7, or 12.

The results show that measurable amounts of vitamin E acetate waspresent in the tears of rabbit eyes for at least 12 days, showing theliquid depot was present in the eye for at least 12 days despite normallacrimal and eye functions; but vitamin E acetate was not present in theanterior chamber of the eye, showing that the liquid depot was notabsorbed into the eye.

Example 2. Comparison of Dexamethasone In Vitro Release

This Example compares in vitro release of dexamethasone power with twoliquid formulations of dexamethasone (one using tocopherol, one usingMIGLYOL®). The percent dexamethasone released from 5 mg dexamethasonepowder, 10% dexamethasone (5 mg) in MIGLYOL® 810, or 10% dexamethasone(5 mg) in tocopherol acetate was tested in a 100 mL saline sink (50 mLexchange). The results are shown graphically in FIG. 4.

Example 3. Liquid Depot Comprising Dexamethasone

Vitamin E is viscous, having a cP (mPas) of approximate 6000-6500 (20°C.). In combination with a liquid film-forming excipient, in thisExample MIGLYOL®, sustained release liquid depots comprising one or moreof a number of pharmaceutical agents can be achieved. MIGLYOL® is thebrand name for a suite of stable neutral oils that are designatedgenerally recognized as safe (GRAS) by the United States Food and DrugAdministration.

A liquid depot was prepared by thoroughly mixing 10% dexamethasone, 72%vitamin E acetate, and 18% MIGLYOL® 810, (10% dexamethasone in 90% of amixture of 80:20 tocopheryl)acetate:MIGLYOL®). Thisdexamethasone-containing liquid depot had a viscosity of 850 cP-860 cP.A 50 μL aliquot was placed in 200 mL saline solution, then 100 mLwithdrawn (and replaced with 100 mL fresh saline) at intervals, and theamount of dexamethasone determined by UPLC. The release profile of thisformulation is shown in FIG. 5 (n=6, repetitions A-F); dexamethasone wasreleased over ten days.

Another embodiment of a liquid depot was prepared by thoroughly mixing10% dexamethasone, 72% vitamin E acetate, and 18% MIGLYOL® 810. Theviscosity was measured in duplicate and indicated viscosity of 995 cPand 1008 cP (average 1001.5 cP); after three months, viscosity wasmeasured at 1079 cP (average of all time points 1027 cP).

Example 4. In Vivo Release from Liquid Depot Comprising Dexamethasone

A formulation of dexamethasone:vitamin E acetate:MIGLYOL® 810 at aweight ratio of 10:72:18 was prepared. In a good laboratory practices(GLP) study, depots of 50 μL were instilled into each eye of New ZealandWhite (NZW) rabbits (either sex, 3.5-4 kilo), and the anterior chambertapped subsequently and assayed by LCMS. The following Table 2 showsdata and number of animals (N) per time point; and the results fordexamethasone detected in the anterior chamber are shown in FIG. 6.

TABLE 2 Average dexamethasone level (ng/mL) in anterior chamber Day 1 35 7 10 Dexamethasone 6.68 6.48 4.14 4.08 3.20 N 5 4 5 15 8

Example 5. Liquid Depot Delivery of Dexamethasone to the Interior of theEye

A liquid depot was assembled by thoroughly mixing 80 mg tocopherylacetate with 20 mg MIGLYOL® 810 (neutral oil). Ten (10) mg dexamethasonewas suspended in 90 mg of the liquid depot, and the formulation mixed toa homogeneous liquid. The dexamethasone liquid depot was sterilized byradiation using standard protocols.

One 25 μL unit of the dexamethasone-liquid depot was instilled into theeyes of female New Zealand White rabbits. Subsequently, the amount ofdexamethasone present in the eye tissues and fluids was determined attime points from 8 hours to 21 days. The data are shown in Table 3 andTable 4:

TABLE 3 Dexamethasone concentration (ng/mL, ng/g) in eye fluids andcornea Aqueous Humor Cornea Conc. Average Tissue Homog. Homog. TissueAverage Time ID Eye (ng/mL) (±SD) (g) (mL) (ng/mL) (ng/g) (±SD) Hr 8 1OD 56.9 44.8 ± 0.058 0.291 203 1015 560 ± 291 OS 53.3 13.7 0.066 0.332157 785 2 OD 48.5 0.051 0.256 107 535 OS 55.0 0.063 0.316 92.0 460 3 OD25.1 0.056 0.282 49.2 246 OS 30.1 0.069 0.347 64.3 322 Hr 24 4 OD 2.802.47 ± 0.076 0.380 88.1 441 260 ± 132 OS 5.00 1.35 0.083 0.417 28.4 1425 OD 2.17 0.077 0.387 81.6 408 OS 1.94 0.059 0.294 46.0 230 6 OD 1.210.073 0.364 30.0 150 OS 1.69 0.071 0.354 37.4 187 Day 3 7 OD BLOQ 2.50 ±0.068 0.340 38.9 195 176 ± 111 OS 0.507 2.54 0.063 0.313 13.5 67.5 8 OD5.41 0.081 0.407 34.2 171 OS 0.667 0.069 0.345 9.89 49.5 9 OD 5.16 0.0990.494 43.8 219 OS 0.779 0.067 0.334 70.6 353 Day 8 10 OD BLOQ 7.53 ±0.062 0.310 16.5 82.5 284 ± 215 OS 13.8 ND 0.083 0.417 27.0 135 11 ODBLOQ 0.057 0.287 46.7 234 OS 1.26 0.076 0.381 99.3 497 12 OD BLOQ 0.0570.283 121 605 OS BLOQ 0.083 0.417 30.3 152 Day 14 13 OD BLOQ ND 0.0780.393 1.39 6.95 OS BLOQ 0.076 0.378 0.837 4.19 14 OD BLOQ 0.064 0.3224.35 21.8 12.2 ± 6.33 OS BLOQ 0.109 0.544 2.20 11.0 15 OD 0.677 0.0800.396 2.69 13.5 OS BLOQ 0.073 0.365 3.19 16.0 Day 21 16 OD BLOQ ND 0.0660.328 0.698 3.49 8.14 ± 6.65 OS BLOQ 0.094 0.468 3.60 18.0 17 OD BLOQ0.056 0.279 1.09 5.45 OS BLOQ 0.071 0.354 1.12 5.60

TABLE 4 Dexamethasone concentration (ng/mL, ng/g) in conjunctiva andiris/ciliary body Conjunctiva Iris/Ciliary Body Tissue Homog. Homog.Tissue Average Tissue Homog. Homog. Tissue Average Time ID Eye (g) (mL)(ng/mL) (ng/g) (±SD) (g) (mL) (ng/mL) (ng/g) (±SD) Hr 8 1 OD 0.085 0.426317 1585 1659 ± 838  0.072 0.357 30.0 150  123 ± OS 0.072 0.359 637 31850.089 0.447 22.5 113 33.9 2 OD 0.099 0.494 295 1475 0.065 0.326 31.4 157OS 0.068 0.342 308 1540 0.067 0.337 30.2 151 3 OD 0.097 0.484 120 6000.081 0.405 16.6 83.0 OS 0.116 0.578 314 1570 0.069 0.345 17.2 86.0 Hr24 4 OD 0.118 0.588 337 1685 598 ± 582 0.047 0.234 2.09 10.5 12.3 ± OS0.091 0.454 77.7 389 0.101 0.504 2.18 10.9 4.87 5 OD 0.207 1.00 138 6900.067 0.337 4.17 20.9 OS 0.123 0.614 29.5 148 0.069 0.347 3.03 15.2 6 OD0.148 0.742 117 585 0.095 0.476 1.66 8.30 OS 0.104 0.519 17.9 89.5 0.0910.457 1.66 8.30 Day 3 7 OD 0.160 0.801 19.7 98.5 0.072 0.357 1.26 6.30OS 0.123 0.613 27.0 135 0.086 0.432 0.594 2.97 8 OD 0.172 0.860 126 630372 ± 369 0.182 0.910 0.753 3.77 9.72 ± OS 0.153 0.765 11.4 57.0 0.0920.459 0.498 2.49 13.31 9 OD 0.137 0.684 198 990 0.026 0.128 7.26 36.3 OS0.129 0.646 64.5 323 0.070 0.348 1.30 6.50 Day 8 10 OD 0.092 0.459 128640 1630 ± 1989 0.070 0.352 1.07 5.35 8.15 ± OS 0.068 0.340 49.4 2470.079 0.396 0.533 2.67 6.80 11 OD 0.129 0.644 122 610 0.067 0.334 0.6513.26 OS 0.125 0.623 402 2010 0.065 0.325 2.85 14.3 12 OD 0.153 0.7671100 5500 0.082 0.408 3.80 19.0 OS 0.065 0.326 155 775 0.083 0.417 0.8754.38 Day 14 13 OD 0.157 0.787 1.80 9.00 53.8 ± 63.2 0.075 0.376 BLOQ ND1.47 ± OS 0.174 0.868 2.04 10.2 0.079 0.396 BLOQ ND 0.459 14 OD 0.0890.445 4.02 20.1 0.069 0.347 0.239 1.20 OS 0.116 0.583 4.08 20.4 0.0860.429 BLOQ ND 15 OD 0.152 0.759 32.2 161 0.069 0.347 0.241 1.21 OS 0.1340.671 20.4 102 0.091 0.456 0.399 2.00 Day 21 16 OD 0.096 0.482 8.48 42.428.2 ± 18.7 0.099 0.493 BLOQ ND 3.88 ± OS 0.158 0.788 9.15 45.8 0.0690.346 1.33 6.65 ND 17 OD 0.199 0.993 3.28 16.4 0.086 0.431 BLOQ ND OS0.190 0.950 1.62 8.10 0.076 0.378 0.222 1.11 Limit of quantitation: 0.5ng/mL for humors, 0.2 ng/mL for tissues; BLOQ: below limit ofquantitation; Homog: homogenate; OD: right eye; OS: left eye; SD:standard deviation; ND: not determined.

These data show that one instillation of the liquid depot resulted indexamethasone in the conjunctiva, cornea, and iris/ciliary body (ICB)for at least 21 days; and in the aqueous humor for at least 8 days (morethan a week). Importantly, this liquid depot was able to deliverdexamethasone to the interior liquid (humors) and tissues (iris/ciliarybody) for at least a week (at least 7 days).

Example 6. Liquid Depot Comprising Prednisolone

A liquid depot was prepared by thoroughly mixing 10% prednisolone, 80%vitamin E acetate, and 20% MIGLYOL® 810, (10% prednisolone in 90% of amixture of 80:20 tocopheryl acetate:MIGLYOL® 810). An in vitro sustainedrelease study of prednisolone was carried out using Cabone rings (WiltonBrands LLC, Woodridge, Ill. 60517) with an outer dimension (OD) of 0.5inch and an inner dimension (ID) of 0.281 inch. Samples, GTH-64A toGTH-64F, each weighing at 50.9 mg, 48.6 mg, 50.4 mg, 48.7 mg, 51.6 mg,and 49.3 mg, respectively (average weight=49.92; SD=1.24; RSD (relativestandard deviation)=2.47) were each separately added into a 125 mL urinesample cup (with cap) containing 100 gm of water. A 0.5″ Cabone ring wasplaced inside the cup. At each time point, 60 ml from each of the sixsamples was withdrawn for sampling and replaced with 60 ml saline. Theamount of prednisolone released was determined by UPLC. The releaseprofile of prednisolone-containing liquid depot formulation is shown inFIG. 7; prednisolone was released for at least 5 days.

TABLE 5 Prednisolone cumulative % released Time GTH- GTH- GTH- GTH- GTH-GTH- % (Days) 64A 64B 64C 64D 64E 64F Avg SD RSD 0 0 0 0 0 0 0 1 32.328.7 31.4 33.9 31.1 28.5 31.0 2.1 6.8 2 56.9 53.5 57.3 59.9 56.1 58.157.0 2.1 3.7 3 78.2 72.7 76.8 79.6 75.9 76.2 76.6 2.3 3.0 4 93.5 88.190.8 92.4 89.2 90.6 90.7 2.0 2.2 5 97.9 93.8 95.9 97.8 96.3 96.4 96.41.5 1.6

Another prednisolone liquid depot was prepared by thoroughly mixing 10%prednisolone, 80% vitamin E acetate, and 20% Miglyol® 810, (10%prednisolone in 90% of a mixture of 80:20 tocopheryl acetate:Miglyol®810). An in vitro sustained release study of prednisolone was carriedout using a 12.7 mm Cabone ring (Wilton Brands LLC, Woodridge, Ill.).Six samples, 5A to 5F, each weighing at 48.2 mg, 48.5 mg, 48.1 mg, 49mg, 51.7 mg, and 49.2 mg, respectively (average weight=49.1 mg; SD=1.34;% RSD=2.7) were incubated in 50 ml saline at 40° C. At each time point,25 ml from each of the six samples was withdrawn for sampling andreplaced with 25 ml saline. The amount of prednisolone released wasdetermined by UPLC. The release profile of prednisolone-containingliquid depot formulation is shown in Table 6-Table 8 and FIG. 8;prednisolone was released for at least 5 days.

TABLE 6 Prednisolone cumulative % released Time % (Days) 5A 5B 5C 5D 5E5F Avg SD RSD 0 0 0 0 0 0 0 0 1 34.8 32.5 32.6 33.9 31.9 33.5 33.2 1.13.2 2 56.9 56.6 54.8 57.2 56.0 58.5 56.7 1.3 2.2 3 76.5 75.4 72.5 73.477.0 77.7 75.4 2.1 2.8 4 88.0 85.1 86.8 85.9 88.9 88.4 87.2 1.5 1.7 592.0 90.0 91.9 93.6 90.6 91.6 91.6 1.2 1.4

TABLE 7 Amount of prednisolone released (μg) Time % (Days) 5A 5B 5C 5D5E 5F Avg SD RSD 1 1678.5 1576.0 1568.0 1659.0 1650.0 1650.0 1630.3 46.42.8 2 1065.3 1167.0 1065.5 1145.0 1246.5 1229.5 1153.1 77.7 6.7 3 942.8915.0 852.8 792.8 1086.3 944.8 922.4 99.5 10.8 4 556.0 471.3 689.3 611.5612.0 525.0 577.5 76.6 13.3 5 64.1 79.3 82.3 126.3 29.3 52.3 72.3 32.845.4

TABLE 8 Average concentration of prednisolone released Time (Days) Avg(μg/mL) SD % RSD 1 32.6 0.9 2.8 2 39.4 1.7 4.3 3 38.1 2.6 6.8 4 30.6 1.75.6 5 19.6 1.7 8.6

Example 7. Liquid Depot Comprising Loteprednol

A liquid depot was prepared by thoroughly mixing 10% loteprednol, 80%vitamin E acetate, and 20% MIGLYOL® 810, (10% loteprednol in 90% of amixture of 80:20 tocopheryl acetate:MIGLYOL® 810). The in vitrosustained release study of loteprednol was carried out by incubating twosamples, 66-A and 66-B, each weighing at about 71.8 mg and 59.8 mg,respectively in 100 mL of 40% methanol/water at 37° C. At each timepoint, 50 ml from each of the two samples was withdrawn for sampling andreplaced with 50 mL of 40% methanol/water. The amount of loteprednolreleased was determined by UPLC. The release profile ofloteprednol-containing liquid depot formulation is shown in Table 9,Table 10, and FIG. 9; loteprednol was released for at least 14 days.

TABLE 9 Average concentration of loteprednol released Total Sample μg/Total Release/ release ID Day μg/mL 100 mL Release day (μg) (%) 66-A1 110.89 1089.0 1089.0 1089.0 15.2 66-A2 3 13.33 788.5 1877.5 394.3 26.166-A3 7 18.30 1163.5 3041.0 290.9 42.4 66-A4 10 15.80 665.0 3706.0 221.751.6 66-A5 14 15.85 795.0 4501.0 198.8 62.7 66-B1 1 8.12 812.0 812.0812.0 13.6 66-B2 3 13.90 984.0 1796.0 492.0 30.0 66-B3 7 17.94 1099.02895.0 274.8 48.4 66-B4 10 10.45 148.0 3043.0 49.3 50.9 66-B5 14 14.93970.5 4013.5 242.6 67.1

TABLE 10 Loteprednol cumulative % released Time (Days) 66-A 66-B Avg SD% RSD 1 15.2 13.6 14.4 1.1 7.8 3 26.1 30.0 28.1 2.7 9.8 7 42.4 48.4 45.44.3 9.4 10 51.6 50.9 51.3 0.5 1.0 14 62.7 67.1 64.9 3.1 4.8

Example 8. Liquid Depots Comprising Prednisone, Triamcinolone, orFluorometholone

Prednisone is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Triamcinolone is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Fluorometholone is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Example 9. Liquid Depot Comprising Moxifloxacin

Moxifloxacin was loaded into a depot of tocopherol and MIGLYOL® as inExample 3, and in vivo sustained release data were collected as inExamples 3-5. More specifically, two liquid depots were prepared: onecontaining 15% (wt %) moxifloxacin (the balance 70:30 EA:MIGLYOL® 810N), one containing 20% (wt %) moxifloxacin (the balance 70:30EA:MIGLYOL® 810 N). One drop of liquid depot was instilled into each eyeof several test rabbits, and tears collected on days 1, 3, and 7.Moxifloxacin was identified and quantified in tear samples by LC/MS/MS.FIG. 10 evidences the amount of moxifloxacin in rabbit tears on days 1,3, and 7 after a single instillation of either 15% (♦) or 20% (▪)moxifloxacin-containing liquid depots. Moxifloxacin was detected in tearsamples 7 days after a single application, showing that the liquiddepots provided therapeutic dosing on the surface of the eye for atleast 7 days. Aqueous humor was also tapped on days 1, 3, and 7. FIG. 11evidences the amount of moxifloxacin in the anterior chamber on days 1,3, and 7 after a single instillation of either 15% (♦) or 20% (▪)moxifloxacin-containing liquid depots. Moxifloxacin was detected inaqueous humor samples 7 days after a single application, showing thatboth liquid depots provided therapeutic dosing in the anterior chamberof the eye for at least 7 days.

Example 10. Liquid Depots Comprising Ciprofloxacin

A liquid depot was prepared by thoroughly mixing 15% ciprofloxacinhydrochloride, 70% vitamin E acetate, and 30% MIGLYOL® 810, (15%ciprofloxacin in 85% of a mixture of 70:30 tocopheryl acetate:MIGLYOL®810). The in vitro sustained release study of ciprofloxacin was carriedout using a Cabone ring of 12.7 mm. Six samples, Cipro-24A to Cipro-24F,each weighing at 50.2 mg, 54.1 mg, 56.3 mg, 44 mg, 62.3 mg and 61 mg,respectively (average weight=54.65 mg; SD=6.857; % RSD=12.5) wereincubated in 50 mL saline at 40° C. At each time point, 25 ml from eachof the six samples was withdrawn for sampling and replaced with 25 mLsaline. The amount of ciprofloxacin released was determined by UPLC. Therelease profile of ciprofloxacin-containing liquid depot formulation isshown in Table 11, Table 12, and FIG. 12; ciprofloxacin was released forat least 24 hours.

TABLE 11 Ciprofloxacin cumulative % released Time 24- 24- 24- 24- 24-24- % (Hours) A B C D E F Avg SD RSD 0 0 0 0 0 0 0 0 2 36.5 40.1 37.424.4 44.1 40.0 37.1 6.7 18.2 6 48.1 47.9 43.3 63.5 75.0 46.2 54.0 12.523.1 24 73.0 71.5 76.7 67.2 77.8 85.2 75.2 6.2 8.2

TABLE 12 Average concentration of ciprofloxacin released Time (Hours)Avg (ug/mL) SD % RSD 2 61.8 17.2 27.9 6 57.7 22.3 38.6 24 64.5 19.6 30.3

Example 11. Liquid Depot Comprising Ciprofloxacin

Another liquid depot comprising ciprofloxacin similar to Example 8 wasprepared by thoroughly mixing 15% ciprofloxacin hydrochloride, 70%vitamin E acetate, and 30% MIGLYOL® 810, (15% ciprofloxacin in 85% of amixture of 70:30 tocopheryl acetate:MIGLYOL® 810). The in vitrosustained release study of ciprofloxacin was carried out using a 12.7 mmCabone ring. Six samples, Cipro-25A to Cipro-25F, each weighing at 45.8mg, 48.5 mg, 51.2 mg, 48 mg, 62.2 mg, and 49.3 mg, respectively (averageweight=50.83 mg; SD=5.839; % RSD=11.5) were incubated in 50 mL saline at40° C. At each time point, 25 ml from each of the six samples waswithdrawn for sampling and replaced with 25 mL saline. The amount ofciprofloxacin released was determined by UPLC. The release profile ofciprofloxacin-containing liquid depot formulation is shown in Table 13,Table 14, and FIG. 13; ciprofloxacin was released for at least 24 hours.

TABLE 13 Ciprofloxacin cumulative % released Time 25- 25- 25- 25- 25-25- % (Hours) A B C D E F Avg SD RSD 0 0 0 0 0 0 0 0 3 49.6 48.0 40.540.9 45.9 37.0 43.7 4.9 11.3  6 89.3 90.8 86.7 82.2 85.7 88.7 87.2 3.13.5 24 91.8 93.0 86.0 95.5 88.4 91.4 91.0 3.4 3.7

TABLE 14 Average concentration of ciprofloxacin released Time (Hours)Avg (ug/mL) SD % RSD 3 66.6 10.9 16.4 6 99.6 10.7 10.7 24 55.5 6.9 12.4

Example 12. Liquid Depots Comprising Gatifloxacin

A liquid depot was prepared by thoroughly mixing 10% gatifloxacin, 70%vitamin E acetate, and 30% MIGLYOL® 810, (10% gatifloxacin in 90% of amixture of 70:30 tocopheryl acetate:MIGLYOL® 810). The in vitrosustained release study of gatifloxacin was carried out using a Cabonering (Wilton Brands LLC, Woodridge, Ill. 60517) of 12.7 mm. Six samples,Gati-90A to Gati-90F, each weighing at 48.2 mg, 48 mg, 48.9 mg, 47 mg,49.1 mg, and 47.8 mg, respectively (average weight=48.17 mg; SD=0.766; %RSD=1.6) were incubated in 40 mL saline at 40° C. [At each time point,20 ml from each of the six samples was withdrawn for sampling andreplaced with 20 mL saline. The amount of gatifloxacin released wasdetermined by UPLC. The release profile of gatifloxacin-containingliquid depot formulation is shown in Table 15, Table 16, and FIG. 14;gatifloxacin was released for at least 24 hours.

TABLE 15 Gatifloxacin cumulative % released Time 90- 90- 90- 90- 90- 90-% (Hours) A B C D E F Avg SD RSD 1 30.7 33.7 32.5 29.7 35.8 31.2 32.32.2 6.9 3 68.8 70.8 67.2 60.4 73.1 65.1 67.5 4.5 6.6 24  81.7 88.9 84.484.0 92.3 85.9 86.2 3.8 4.4

TABLE 16 Average concentration of gatifloxacin released Time (Hours) Avgμg/mL SD % RSD 1 38.9 3.2 8.2 3 61.9 5.0 8.1 24 53.4 3.2 6.0

Example 13. Liquid Depots Comprising Anti-Infectives (e.g.,Levofloxacin, Gentamicin, Tobramycin or Chloramphenicol)

Levofloxacin is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Gentamicin is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Tobramycin is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Chloramphenicol is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Example 14. Liquid Depots Comprising Anti-Allergy Agents

Ketotifen is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Lodoxamine is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Azelastine is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Olopatadine is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Epinastine is loaded into a depot of tocopherol and MIGLYOL® as inExample 3. In vitro and in vivo sustained release data are collected asin Examples 3-5.

Example 15. Liquid Depot Comprising Latanoprost

Latanoprost was loaded into a liquid depot of 80:20 tocopherylacetate:Miglyol® 812 at two different concentrations as described hereinto provide sustained release formulation A (0.05% latanoprost in 80:20EA:Miglyol® 812) and formulation B (0.03% latanoprost in 80:20EA:Miglyol®812). A commercial formulation, Xalatan® (latanoprostophthalmic solution) 0.005%, was used as a comparator. Xalatan®(latanoprost ophthalmic solution) 0.005% is supplied as a sterile,isotonic, buffered aqueous solution of latanoprost with a pH ofapproximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Onedrop of Xalatan® vs 50 μL of formulation A or B was instilled once inthe eyes of 4.0-4.5 kg NZW rabbits. Samples from the anterior chamberwere collected, four eyes per time point, and the concentration oflatanoprost acid determined as described herein. As shown in FIG. 15, aone-time 50 μL instillation of formulation B (0.03% latanoprost)provided detectable latanoprost acid in the anterior chamber for atleast 7 days; a one-time 50 μL instillation of formulation A (0.05%latanoprost) provided detectable latanoprost acid in the anteriorchamber for at least 15 days.

Example 16. Liquid Depot Comprising a NSAID

A formulation of the NSAID diclofenac was prepared by thoroughly mixing10% diclofenac acid in a 90% liquid depot mixture of 80:20 tocopherylacetate:Miglyol®. A one-time application of 50 μL of this formulationwas instilled into the eyes of NZW rabbits, and then tear samples werecollected and analyzed as described herein. The results, as shown inFIG. 16, indicate that diclofenac was detected in the rabbit tear filmfor a least 7 days.

Example 17. Liquid Depot Comprising Cyclosporin

Two formulations comprising 2% cyclosporin A (CsA) were prepared asprovided herein. One formulation contained 2% CsA in a mixture of 90:10tocopheryl acetate:Miglyol® 812; the other contained 2% CsA in a mixtureof 70:30 tocopheryl acetate:Miglyol® 812. The in vitro release (% CsArelease) was monitored as described herein, and the total % release ofCsA plotted over the course of at least 120 days, as shown in FIG. 17.

Example 18. Liquid Depot Applications

A sustained-release liquid depot loaded with a therapeutic agent isadministered as a single application or provided in form of a kit to asubject who wears contact lens or make up. Because of the physicalconsistency, no running of the liquid depot is observed in the subject'seyes. In addition, the subject does not experience blurring of vision oreye irritation. Accordingly, at least one embodiment provides a kitcomprising at least one single-use dispenser, wherein the at least onesingle-use dispenser comprises the liquid depot as described herein.

1. A liquid depot for sustained release of an active agent in the eye,the liquid depot comprising: a tocopherol; an ocular film-formingexcipient; and an active agent; wherein the liquid depot has a viscosityof about 850 cP to about 1100 cP, inclusive.
 2. The liquid depot ofclaim 1, wherein the tocopherol is α-, β-, γ- or δ-tocopherol, or α-,β-, γ- or δ-tocotrienol.
 3. The liquid depot of claim 1, wherein thetocopherol is an α-, β-, γ-, or δ-tocopherol.
 4. The liquid depot ofclaim 1, wherein the tocopherol is tocopheryl acetate.
 5. The liquiddepot of claim 1, wherein the ocular film-forming excipient consists ofmedium-chain triglycerides.
 6. The liquid depot of claim 1, wherein theactive agent is a corticosteroid.
 7. The liquid depot of claim 6,wherein the corticosteroid is a member selected from the groupconsisting of dexamethasone, prednisolone, prednisone, loteprednol,triamcinolone and fluorometholone.
 8. The liquid depot of claim 7,wherein the liquid depot comprises (a) about 10% dexamethasone; and (b)about 90% of a mixture of tocopheryl acetate:medium-chain triglyceridesat a ratio of about 90:10 to about 60:40.
 9. The liquid depot of claim5, wherein the liquid depot comprises, on a wt % basis, (a) about 10%prednisolone and (b) about 90% of a mixture of tocopherylacetate:medium-chain triglycerides at wt/wt a ratio of about 80:20. 10.The liquid depot of claim 7, wherein the liquid depot comprises, on a wt% basis, (a) about 10% loteprednol and (b) about 90% of a mixture oftocopheryl acetate:medium-chain triglycerides at wt/wt a ratio of about80:20.
 11. The liquid depot of claim 1, wherein the active agent is ananti-infective.
 12. The liquid depot of claim 1, further comprising ananti-infective.
 13. The liquid depot of claim 11, wherein theanti-infective is moxifloxacin.
 14. The liquid depot of claim 12,wherein the liquid depot comprises (a) about 10%-20% moxifloxacin; and(b) about 80%-90% of a mixture of tocopheryl acetate:medium-chaintriglycerides at a ratio of about 70:30.
 15. The liquid depot of claim12, wherein the liquid depot comprises, on a wt % basis (a) about 15%ciprofloxacin; and (b) about 85% of a mixture of tocopherylacetate:medium-chain triglycerides at a ratio of about 70:30.
 16. Theliquid depot of claim 12, wherein the liquid depot comprises, on a wt %basis (a) about 10% gatifloxacin; and (b) about 90% of a mixture oftocopheryl acetate:medium-chain triglycerides at a ratio of about 70:30.17. The liquid depot of claim 1, comprising dexamethasone andmoxifloxacin in a mixture of tocopheryl acetate:medium-chaintriglycerides at a ratio of about 90:10 to about 60:40.
 18. The liquiddepot of claim 1, wherein the liquid depot is disposed within asingle-use dispenser.
 19. A kit comprising at least one single-usedispenser, wherein the at least single-use dispenser comprises theliquid depot of claim
 1. 20. A method of treating a malady of the eye ina subject in need thereof, comprising topically administering to the eyeof the subject a liquid depot comprising (a) at least one active agent;and (b) a mixture of mixture of tocopheryl acetate:medium-chaintriglycerides at a weight ratio of about 90:10 to about 60:40. 21-26.(canceled)
 27. A liquid depot comprising: a tocopherol; an ocularfilm-forming excipient; and, optionally, an active agent; wherein theliquid depot has a viscosity of about 850 cP to about 1100 cP,inclusive. 28-33. (canceled)